Method of making hydrazine derivatives



METHOD OF MAKING HYDRAZINE DERIVATIVES Bernard Rudner, Silver Spring,Md., assignor to W. R.

Grace & Co., New York, N.Y., necticut No Drawing. Filed June 13, 1957,ser. No. 665,605

12 Claims. or. 260-2945) a corporation of Con- This invention relates toa novel method for preparing salts of basic hydrazine derivatives inwhich at least one nitrogen has both of its hydrogens replaced by eithertwo substituted carbon atoms each singly bonde'dgto the nitrogen or onesubstituted carbon atom doubly bonded to the nitrogen atom. In onespecific aspect, it relates to the preparation of quaternizedp-hydroxyalkyl-containing hydrazinium salts and their derivatives. Inanother aspect, it relates to the reaction of acid salts of substitutedhydrazines and oxiranes to form novel hydrazinium 'salts.

For a long time the useful and interesting quaternary hydrazinium saltscould be prepared only on a laboratory scale. The common method ofmaking these compounds comprised the reaction of 1,1-disubstitutedhydrazines and alkylating agents, viz: methyl halides. Because of theformer difiiculties involved in preparing the parent hydrazines and thelimitations of the final, alkylation 1 can be hydrogen alkyl,-cycloalkylaryl, and aralkyL (see 0. Westphal, Berichte de Deutsche Chemische'Geselschaft 74: 759 et. seq., 1365, et. seq. (1941)), the uses of thehydrazinium chlorides have been explored only to a limited extent. Thesevarious uses include commercial application as bacteriocides,detergents, polymerization initiators, catalysts, antihistaminics,anti-spasmodics, curarimimetics and a Wide range of intermediates.

Unfortunately, the effectiveness of the method used by Westphal islimited primarily to the production of a ice X as used in the aboveequations, and hereafter in the specification, may be an anion of thefollowing types: chloride, bromide, iodide,- sulfate, phosphate,nitrateg benzenesulfonate, monomethyl sulfate, monophenyl phosphate, andfunctionally'equivalent materials. The possible substituents attached tothe free bonds become apparent from the ensuing discussion.Productsmade-by the methods indicated above can be generically describedas fl-hydroxyalkylhydrazinium, hydrazonium and azinium salts. Thereaction products in each case are probably a mixture of isomers. Forexample, in Equation 4,5 action similar to Equation 1, the followingproducts are obtained:

In the formulas shown in Equation 4, the values of R R2, R3, R4, R5 andR are these. R1, R2, R3 and R addition to representing the individualsubstituents atone said, R can be a carbon-containing residue which istaken collectively with R or R to form mono or bicyclic carbon ringstructures having no more than 7 annular members in a ring, for example,vinylcyclohexene dioxide.

variety of aliphatic hydrazinium salts, since more com- 1 plexalkylating agents, e.g. the hydroxysubstituted alkyl ating agents, arenot readily available. For example, while the simplel,l-dimethyl-l-(2-hydroxyethyl) -hydra zinium bromide is readilyobtainable from ethylene bromohydrin and l,1-dimethylhydrazine, thehomologous 1,l-dimethyl-l-(2-hydroxyoctadecyl-1) hydrazinium bromidecould not be readily prepared by a similar procedure because thecorresponding bromohydrin is unavailable. I have found an alternativemethod which produces with great facility this latter class ofhydrazinium salts. In

R and R can be lower alkyl, hydroxyl lower alkyl or carbon-containingresidues which when taken collectively with each other represent thenecessary atoms to com plete a heterocyclic ring structure having atleast 5 and not more than 7 endocyclic atoms, e.g., a pyrrolidino,morpholino, or heptamethylenimino residue. When R is lower alkyl, R canbe'a benzene, nitrobenzene, or chlorobenzene residue. X has the valuesindicated afore; said in Equations 1, 2 and 3. i

I have previously mentioned that the reaction of Equation 4 involves theuse of oxiranes, commonly referred to as olefin oxides, epoxides orepoxy compounds. These readily available compounds are highly reactiveliquids or solids. The most common of the oxiranes, ethylene oxide, ismade in quantities of thousandsof tons per year for use in makingdetergents, glycols, waxes and the like. Commercially, the oxiranes areprepared generally by the oxidation of an olefin, e.g. either in air inthe presence of silver catalyst or with a peracid such'as per aceticacid. The Darzens reaction also affords a simple Fundamentally, myinvention comprises the reaction atom doubly bonded to the nitrogenatom. The broad scope of this new type of reaction is shown below inEquations 1, 2 and 3:

O OH

way of making certain other oxiranes, as illustrated in Equation 5.Values of R R R and R are those indicated aforesaid in connection 'withEquation 4.

Typical useful oxiranes for the purpose of my invention include, but arenot limited to, ethylene oxide base propylene oxide omonom t-butyleneoxide Z-butylene oxide CH;CHCHCH:

isobutylene oxide CHzC----CH:

o 2-'vinylethylene oxide (2-vinyloxirane) CHFCH-CHCH:

I butadiene dioxide CHxCHCHCH:

2',2,3,3-tetramethylethylene oxide,

' CH, CH; 0 Hr- H:

l-octene oxide CH3(CH2)5CHCH2 diisobuty-lene oxide, cyclohene oxidea-pinene oxide, dodecene 2,3-oxide CEa(CH:) -CH-CHC'H;

0 mixed octadecene oxides C H 0, styrene oxide 2-benzyloxirane stilbeneoxide glycidol, epichlorohydrin, glycidic acid, ethyl glycidate, butylepoxyoleate, epoxidized glyceryl trioleate, 2-(mnitrophenyl) oxirane,2-benzoy1-3-pheny1oxirane i Q- -e -Q 4-trifluoromethylstyrene oxide MCGHOH.

tetrahydroxybutylethylene oxide glyceryl triepoxyricinoleate, and thelike. Obviously, the above list is intended to be merely illustrativerather than all inclusive.

The acid salts of substituted hydrazines may be readily preparedaccording to the technique shown in great detail in Example 1. Generallythe method involves treating the selected hydrazine cautiously with theacid which will provide the particular acid salt desired with goodstirring or refluxing. The product may be purified using standardlaboratory methods. Substituted hydrazines may now be readily preparedby the method described by A. D. Kelmers in his PhD thesis submitted tothe Ohio State University (1954). The Kelmers technique involvestreating a primary or secondary amine with chloramine under anhydrousconditions to produce the desired substituted hydrazine. This method hascontributed greatly to the availability of these compounds.

The essential limitations on the choice of substituted hydrazine for myreaction are two. First, the efiectsof steric hindrance in retarding thereaction of the oxirane with the hydrazine salt increase where branchchains and cyclic radicals are attached to the nitrogen where thereaction with the oxirane occurs. As the steric effect increases, theamount of quaternized product which can be obtained by treatment withoxirane declines. Very little, if any, of the desired reaction productis obtained when tertiary carbon atoms are attached directly tothereactive nitrogen. Likewise, hydrazine derivatives having more thanone cyclic group attached univalently directly to one of the nitrogensexhibit relatively little afiinity toward the oxirane. A stericallyhindered N,N-dialkyl hydrazine shows the following reaction:

Steric effects are obvious to the skilled organic chemist, although itis diflicult to draw a line with mathematical exactness which wouldexclude hydrazine salts which are inoperative for the purposes of thepresent invention. A proper limitation, however, takes due cognizance ofthe judgement of skilled chemists. It is suflicient to say that wherethe nitrogens of the substituted hydrazine are blocked by steric eiTectsto the point at which an oxirane will no longer attach thereon,hydrazines of such structure are unsuitable.

The more basic nitrogen or the hydrazine, which acts as the cationiccenter, will be attacked by the oxirane if steric factors do not preventsuch an attack. The desired attack is achieved when alkyl, hydroxyalkyl,and carbon-containing residues which unite to form a ring are thesubstituents of the nitrogen which is the cationic center. On the otherhand, if the substituted nitrogen contains aryl or acyl groups thebasicity of that nitrogen is reduced and the oxirane will tend to attackthe amino group :(the nitrogen having two hydrogen atoms attachedthereto). In spite of this fact, monoacyl or monoaryl 5 substitutedhydrazine salts will react to some extent with oxiranes to producehydrazim'um salts. When my novel type of reaction is considered in itsbroad sense, the problem of basicity becomes increasingly acute.Hydrazones are less basic than hydrazines and azines are less basic thanhydrazones. In the latter case,

compounds such as benzaldehyde azine, which is not1,l-diethyl-Z-acetylhydrazine (ciHmNNI-Iii OH:

1 l-dimethylsemicarb azide CH NNHCONH l-allyl-l-benzylhydrazine CH1:oHomNNH,

mom,

l-ethyl-l -phenethylhydrazine CgH CH CH lTINH,

l-methyl-l-phenylhydrazine oumrfNm l-cyclohexyl-l-ethylhydrazine C a u iN z l-aminopyrrolidine omen;

N NH:|

onion:

4-aminomorpholine C Ha C H:

N--NHz 0 Hz C H2 l-aminopiperidine CH2 N-NH:

l-amino-4-phenylpiperazine 0 Hz C H:

HzNN

1,4-diamino 2-methy1piperazine 0 H5 0 H2 3 H HQNN NNH,

1-amin0-4-b enzoylpip erazine l-aminoperhydroindole Z-methyl-l-phenyl5-pyrazolidone acetaldehyde semicarbazone ll CHaCH:NNHCNHz acetonephenylhydrazone (CH C:NNHC H methylethylketone2,4-dinitrophenylhydrazone N-cyclohexylidenebenzhydrazide 011.011. c CH2CiNNHCCgH cyclohexylidene acetylidene azine fl-methoxypropionaldehydeazine (CH OCH CH CH :N) 2

benzaldazine diethylketone-azine [(C H C:N--] propylidene 2-acetylhydrazone CHaCHgOHiNNHFCH] and the like.

The possible variations of the anion X have been fully v describedhereabove. It is sufficient to say that HX must be capable of splittingthe oxirane ring by simple addition and the additive thus formed must becapable of re acting with a hydrazine derivative. The overallmejcha nismis possibly similar to Equations 7 and 8 shown-hereunder. v

Since my novel reaction is very much faster than that of the simplealkylation of Equation 8, it is obviously not a mere sequence ofEquations 7 and 8. Instead, it appears' more likely that the'first, stepof my novel reactionim volves the formation of an oxonium complex of thehydrazine; viz:

The ratio of oxirane to hydrazine salt used for the purposes of my newreaction is governed to a measurable extent by the required purity ofthe product. If a large excess of oxirane is used a further reactionwill result in the formation of polyoxyalkyl hydrazinium salts. Fordetergent and polymer work such a result is not wholly undesirable.However, in preparing pharmaceutical and drug intermediates the desiredresult is a single, easily purifiable product. For these purposes themole ratio of oxirane to hydrazine salt should be limited to less thanabout 0.95. The limitation is not critical when treating solutions ofthe hydrazine salt with an oxirane in the vapor phase at atmosphericpressure without condensation. In this instance an excess of the oxiraneshould be used to obtain a workable yield.

My reaction is adaptable, depending of course on the nature of thereactants, to gas-liquid, liquid-liquid, gassolid, liquid-solidreactions. It works effectively using both anhydrous and aqueoussolutions. A solvent is usually desirable if the oxirane or hydrazinesalt is not liquefiable, or if the hydrazine salt is too expensive towarrant its use as its own solvent.

The wide range of solvents applicable to my novel reaction includeshydrocarbons, e.g. heptane, cyclohexane, benzene, xylene and the like;ethers, e.g. diethyl ether, diamyl ether, dioxane and anisole; amides,e.g. dimethylformamide and dimethylacetamide; halohydrocarbons, e.g.chloroform, carbon tetrachloride, trichloroethylene, and chlorobcnzene;and nitroaromatics, e.g. nitrobenzene. Hydroxylic solvents such as waterand polar, at least partially water soluble, organic solvents, e.g.,lower alcohols and ethoxyethanol, are especially useful. In general, themore polar the solvent the better the reaction proceeds. However,although water is highly polar and a good solvent, it may tend to reactwith more reactive oxiranes. Again, while nitrobenzene is more polarthan benzene, it reacts at higher temperatures with the hydrazines.Unreactive polar liquids capable of dissolving both reactants are mostdesirable, but it is also possible to use an inert liquid solvent, e.g.,mineral oil, as a reaction medium providing there is a good contactmaintained between the reactants. It is obvious to the trained organicchemist that many other solvents would be equally suitable as reactionmedia.

Practical, rather than theoretical, limits control the reactiontemperature. Thus, ethylene oxide will react, although slowly, evenbelow C. Extremely elevated temperatures favor complicated sidereactions such as further oxyalkylation and dehydration. Thus, thetemperature depends upon the nature of the desired product (i.e.mono-oxyalkylated or polyoxyalkylated) the reactivity of the oxirane andto a lesser extent the reactivity of the hydrazine salt. In general atemperature range of about 20200 C. is satisfactory. Volatile oxiranesshould be reacted at temperatures within the lower portion of the range.

Pressure control is again a matter of convenience rather than necessity.Preferable pressure conditions are those at or very slightly aboveatmospheric pressure; although the allowable maximum extends upwardlytherefrom and is controlled to a large extent to the type of equipmentused. When more sterically hindered oxiranes are used as reactants,increased pressurm up to about psi. are advantageous.

The time required to complete the oxirane-hydrazine. salt reaction isdependent on the aforementioned factors, thoroughness of contact, .andintrinsic process variations apparent to one skilled in the art. Ahighly reactive oxirane will react with an unhindered hydrazine salt atelevated temperatures in a few minutes. 0n the other hand, an unreactiveoxirane may require several hours to react with a sterically hinderedhydrazine salt. The reaction time is conveniently measured by followingthe rate disappearance of one of the components, e.g., the oxirane (bytitration) or the hydrazine salt (by alkaline steam distillation andiodometric titration). Once this. is done, it is easy to establish apractical reaction time per unit batch of affixed reactants.

The reaction of oxiranes with hydrazones or azines are shown below inEquations 9 and 10.

rta OH Rt 0 The values for the R substituents shown above are these: Forthe hydrazone formation (Equation 9) the values of R R R and R are thesame as those shown for the hydrazinium salts in Equation 4. Inaddition, R is hydrogen, loweralkyl, or a carbon-containing residuewhich may be taken collectively with R to complete a ring structurehaving at least 5 and not more than 6 annular carbon atoms. R as anindividual substituent is an alkyl radical of not more than 18 carbonatoms, phenyl, p-tolyl and benzyl. R is a hydrogen, an acyl groupcontaining less than 8 carbon atoms, carbamoyl, thiocarbamoyl, benzyl,phenyl, mono and dinitrophenyl, halophenyl, sulfophenyl, and naphthyl. Ris a hydrogen and benzyl. For the azines (Equation 10) R R R R R and Rhave the values shown above for the hydrazones. R and R have the samevalues as R and R The scope and utility of my invention is furtherillustrated by the following examples:

Example I A g. portion of freshly distilled dimethylhydrazine(equivalent to 2 moles) was cautiously added with good stirring to 500ml. chilled concentrated hydrochloric acid (a 5 mole equivalent) over aperiod of one hour. The reaction mixture was stirred to roomtemperature, then evaporated dry at 12 mm. Hg. When it was observed thatthe flask lost no further Weight on vacuum evaporation, 500 ml. of mixedxylenes were added thereto. Using a Dean-Stark trap, the mixture ofliquids was azeotropically distilled for 24 hours. Water had ceased tobe distilled over about 8 hours before the distillation wasdiscontinued. The resulting mixture was cooled and the xylene wasdecanted off. Vacuum drying at 2 mm. Hg gave 161 g. of a slightly yellowviscous oil which, on

9 being seeded, yielded almost white crystals of dimethyl hydrazinehydrochloride. The product was identified by conversion to its oxalate.

Example II A 9.7 g. portion of the product of Example I in 70 ml. ofrefluxing ethyl alcohol was treated over a period of approximately 30minutes with a total of 5 g. ethylene oxide as a gas bubbled through thesolution. Refluxing was continued for an additional 30 minutes; thesolvent was then stripped off in vacuo. The viscous tan oil remainingweighed 12.2 g. It was washed, with diethyl ether, then vacuum dried.This treatment failed to produce crystals. The material was thenrecrystallized twice from a solvent mixture containing two parts ethylacetate to one part ethyl alcohol. The resulting product appeared ashighly hygroscopic oil-white needles which melted at 157 to 158 C.,representing analytically pure l,l-dimethyl-1-(2-hydroxyethyl)hydrazinium chloride. For purposes of identification it was converted toa picrate melting at 169 C. The novel product was found to be soluble inwater and ethyl alcohol. It showed some solubility in acetone. Thepreparative reaction is shown below in Equation 11.

Example 111 A portion of freshly distilled diethylhydrazine wasconverted to its HBr salt by a procedure substantially similar to thatof Example I. A 73% yield of diethylhydrazine hydrobromide was obtainedthereby.

Example IV The procedure of Example H was substantially duplicated,treating the product of Example III with ethylene oxide in water at 80C. on a steam bath. The aqueous solution was cooled, extracted twicewith benzene, then made weakly alkaline with sodium carbonate. The mix-,ture was re-extracted and then vacuum dried. Recrystallization of thepasty brown residue from ethyl acetate was repeated three times to give92% pure 1,1-diethyl-1- (2-hydroxyethyl) hydrazinium bromide. Theproduct appeared as off-white crystals which decomposed at about 191 C.When treated with picric acid it formed a salt melting at l79179.5 C.after recrystallization.

Example V The reactants of Example II were allowed to react under themodified conditions of Example IV to give as a product a supercooled oilrepresenting about an 85% yield of 1,l dimethyl-1-(2-hydroxyethyl)hydrazinium chloride.

Example VI wasthen adjusted to 88.5 with sodium carbonate. This solutionwas extracted with chloroform andno dimethyl hydrazine appeared in theorganic extract. The solution was then evaporated to dryness andextracted with three 100 ml. portions of isopropyl alcohol which hadbeen previously dried over anhydrous magnesium sulfate. The extract wasthen evaporated dry in vacuo to give 17.1 g. of a thic'k'tan oilrepresenting crude The product was extracted with diethylether andthereafter precipitated from ethyl alcohol with methyl isobutyl ketone.On vacuum drying 14.1 g. of a white semi-solid was obtained. By analysisit appeared to be a mixture of the above product and high oxyethylatedderivatives, apparently V IITH: V 1

j 5 (CH3)2N (C2H40)|;C2H4OH o1- Extraction of the dried product withanhydrous peroxidefree dioxane gave .us the more soluble fraction ahygro-" scopic thick oil. The oily nature of the ultimate productsuggested that it was rich in V I: lIIH 1+ (CHa)aN(CzH40)nCzH4OH Cl-Example VII A solution of 6.7 g. of LI-dimethylhydrazine (0.1 mole of90% pure base) in 500 m1. dry peroxide-free diethyl ether was saturatedfor one-half hour at -10 C. with dry HCl. It was sealed andrefrigeratedfor forty-eight hours. The semi-solid residue obtainedtherefrom by decantation was washed by decantation with absolute,peroxide-free, diethyl ether and vacuum dried to give a 98% yield ofdimethylhydrazine hydrochloride. This material was refluxed in 100 ml.of isopropyl alcohol and then treated with a slow stream containing a1:3 molar mixture of ethylene oxide and nitrogen. A total of 4.8g. of CH O (0.11 mole) was added over a period of 30 minutes. The mixture wasrefluxed for 30 minutes and allowed to cool to room temperature. It wasrefrigerated over night and a solid mixture of product and unreactedhydrochloride was obtained therefrom by filtration. The salt and thefiltrate were poured into 200 ml. of 5% sodium bicarbonate solution, andevacuated dry in vacuum at 40 to 50 C. The residue was extracted withisopropyl alcohol. Crude V [(CHahlTTCzEhOHJOl' NH:

was obtained on adding ether. The product was recrystallized from ethylacetate to give the highly hygroscopic pure hydrazinium chloride in goodyield.

Example VIII A quantity of N-aminomorpholine was prepared by I theprocedure of Knorr and Brownsdon Ber. 35, 4477 (1902). The anhydroushydrochloride of this material was prepared and treated in a mannersimilar to that of Example VII. An 0.01 mole portion of thehydrochloride in 30 ml. of isopropyl alcohol was reacted at 0 to 10 C.with 0.01 mole ethylene oxide as a gaseous mixture. The resultingmixture was stirred continuously for 2 hours and then allowed to warm toroom temperature. It was thereafter refluxed for 30 minutes and thesolvent was stripped oif in vacuo. Using the workup procedure describedin Example VII, a good yield of the product,4-amino-4-(2-hydroxyethyl)morpholinium chloride, having a MP. of 15253C., was obtained.

Example IX N-aminopiperidine, a light brown basic oil with an unpleasantsmell, was prepared by a procedure substantially the same as that usedfor making N-aminomorpholine; supra. Ten grams of the N-aminopiperidinewere 25953 570 11 12 solved in 100 ml. of dry dioxane. This solution waskept tion of the reaction product was charcoaled and evapoat 12 to C.and treated with saturated dry HCl rated dry to give a thick hygroscopicoil, crude 1,1-bis(2- gas. A suspension of the hydrochloride thus formedhydroxyethyl) l-methylhydrazinium chloride. The prodwas held at 80 C.with good agitation for a 30-minute uct was purified by precipitationfrom ethyl alcohol with period to remove most of the excess HCl. Whilekeep- 5 dioxane. The purified oil reacts with benzoyl chloride to ingthe temperature constant, 8.8 g. of glycidol were give a .benzoylderivative melting from 166-166.5 C. added dropwise to a refluxingsolution of the hydrochlo- The preparative reaction is shown hereunderin Equaride for a period of 30 minutes. The reaction mixture tion 14.

( onion,

CH3 BaS O 4 'l Ba Cl: (H O C2114) zN-NHz C1 HUI was stirred for minutesafter addition of the glycidol and refluxed for two additional hours. Itwas chilled Example XII over night, then filtered at 15 C. to give as aproduct 20 A 9.2 g. portion of freshly distilled methylhydrazine highlyhygroscopic crude tan 1-amino-l-(2,3-dihydroxywas reacted with 12 g. ofbenzyl chloride and 250 ml. of propyl) piperidinium chloride. Thisinteresting product diethyl ether at 1520 C. for a period of two weeks.melted at 176 to 178 C. It did not form ahexa- The reaction mixture waswashed with water and dried fluophosphate salt. Equation 12 shows thepreparative for two hours over anhydrous magnesium sulfate. Thereaction: resulting solution was saturated at 10- 15 C. with dryCHz-CHCH OH Example X HCl to give approximately a 30% yield ofl-methyl-l- The similar reaction of glycidol with dimethylhydrazine 1benzylhydrazine hydrochloride hydrochloride gave a highly hygroscopicthick oil, NHZ

-CH2N .HCl [(GIIsh-If-CHzCHOHCHzOHJCl" 011 NHz which failed to give aPR; or picrate precipitate from decomposing at about 200 C. Thehydrochloride, 1 g.,' aqueous solution. Reaction of the oily productwith was mixed with three equivalents of styrene oxide in a excessbenzoyl chloride by a SchottenBaumann reaction small test-tube withconstant stirring. The temperature gave a tribenzoate melting at 89 to91 C. The reaction 45. of the mixture was slowly increased to about 100C., sequence appears hereunder: using a water bath. The mixture wasmaintained at NH; O NH2 3H; 1 NaOH 0 o=( )C6H5 Example XI thistemperature with occasional stirring for two hours. The resulting brownmass was allowed to cool, then A quantity ofl-methyl-1-(2-hydroxyethyl)hydrazine washed by decantation with ethylether. It was suswas prepared essentially according to the teachings ofpended in water and the pH thereof was adjusted to 8.5 Benoit (Bull.Soc. Chimique, France 1947, p. 242). with sodium carbonate. This basicmixture was then Evaporation of this material from an aqueous solutionextracted three times with equal volumes of benzene. The ntaining 0116 qiv of Sulfuric acid P equivalent benzene extracts contained appreciablequantities of of hydrazine gave on vacuum drying the Sulfate as anorganic base which, when treated with HCl, formed a oil-white powder. A0.1 mole portion of this powder in h d hl id l i at 161 .163 C haqueous.

100 ml. of refluxing isopropyl alcohol was treated ith layer andassociated solids were evaporated dry in vacuo 0.11 mole of gaseousethylene oxide in the manner ded the id l brown i tu f oil d lid scribedin the Preceding eXamplfis- The Ramon extracted with isopropyl alcohol.Evaporation of that ture was evaporated to dryness. The residue,suspended t t gave crude 1-benzy1-1.methy1 1-(2..hydr y-2 in water, wasboiled for two hours with an equivalent phenylethyl)hydraziniumchloride, melting at 186-189 C. of barium chloride and allowed to cool.The barium with decomposition. Recrystallization from ethyl acetatesulfate thus formed was filtered ofi. An aqueous solugave brown plateswhich melted at 191193 C. It

of course possible, although less likely, that a portion of the productwas the isomeric l-benzyl-l-methyl-1(2- hydroxy-hphenylethyl)hydrazinium chloride. See the preparative reaction of Equation CHICICH2NNHz.HCl CHaNHNH:

CH Hg Example XIII A 24 g. portion of styrene oxide, 24 g. ofbenzylphenylhydrazine hydrochloride and 1 drop of gamma collidine wereheated to 80-90 C. This mixture gave an exothermic reaction which causedthe temperature to rise to 140 C. It was cooled to 105 C. and kept atthis temperature for 3 hours. During this time the viscosity noticeablyincreased. Extraction of the cooled semisolid with 200 ml. of benzene in4 portons left a crude benzene-insoluble residue which had a meltingpoint of 40 C. and decomposed at 85 C. Extraction of this solid withwater followed by subsequent evaporation, gave a hygroscopic whiteproduct having a melting point of 62 C., presumablyl-phenyl-l-benzyl-ll(Z-hydroxy- 2-phenyl) ethyllhydrazim'um chloride.

This novel compound was soluble in water, it was not precipitated bycaustic addition. It contained ionic chlomine, and in alkaline solutionreadily reduced large quantities of KMnO Example XIV Repetition of theprocedure of Example XIII using 1,1- dimethylhydrazine hydrochloridegave as a product, 1,1- dimethyl-l-l(2-hydroxy 2-phenyl)ethyl]hydrazinium chloride in a better yield than the product of the previousexample. This new compound was a highly hygroscopic. yellow solid. Afterrecrystallization from ethyl acetate, it melted at 146448" C.

Example XV A 0.05 mole portion of dimethylhydrazine hydrochloride wasmixed with an equal molar quantity of 1,2-diisobutylene oxide in a largetest-tube and held in a boilingwater bath over night. The cooled brownmixture was triturated well with diethyl ether and hexane and washed bydecantation. The washed mixture was slurried with water containingsodium carbonate to adjust the pH to 88.5. The mixture was thenreextracted with hexane; the extract was discarded. After evaporatingthe water from the residual mixture, it was taken up in chloroform,washed, dried, and reevapor'ated to give crude 1,1- dimethyl-l(2,4,4-trimethyl-2 hydroxyamyDhydrazinium chloride, a super-cooled oilwhich was not completely solidified on seeding. The oil was purified byprecipitation from isopropyl alcohol withethyl ether. It was found to besoluble in chloroform, and quite soluble in water, ethanol and acetone.

c Example XVI v The procedure of Example XV was substantially repeatedusing vinylcyclohexane dioxide, made by epoxida- CHs tion of4-vinylcyclohexene, as a reactant. The reaction mixture was exceedinglycomplex. From the water-soluble, ethyl acetate-insoluble portion wasobtained a highly hygroscopic oil, the reactions of which indicated-thatit was a mixture of CHOHCHQOH (error-N and ,HO -CH! 1 I ononomr r-om(CHQF I 1 1E: oh

A soft paste was obtained from the water-soluble, ethylacetate-solubleoily fraction by ether extraction. This somewhat hygroscopic material isbelieved to be a poly mer containing combined hydrazinium hydrochlorideresidues, possibly of the structure shown below Example X VII 'Theprocedure of Example XV was substantially repeated using a commerciallyavailable mixture consist ing of approximately pure epoxides of theformula Example XVIII The procedure of Example XV was substantiallyrepeated using a technical grade dioxirane availablecommercially asDiepoxy Ester #1 considered to be primarily:

Two parts dimethylhydrazine hydrochloride were used per one part of thedioxirane. After the reaction period was over, the resulting mixture wasfound to be almost entirely water soluble. It was completely soluble inchloroform and xylene. From the diethyl ether-soluble, hexane-insolubleportion was obtained a mixture of product containing one hydraziniumchloride residue which is believed to have the following structure:

From'the ether-insoluble, ethyl acetate-soluble portion was obtained amixture containing:

and its isomers.

Example XIX The procedure of Example XV was substantially repeated usingthree equivalents of dimethyl hydrazine hydrochloride and a glyceridecommercially available as Epoxy Acetoxy Stearin. This reactant appearsas a bright mobile liquid having as its major active ingredient theglyceryl tri-ester of acetoxyepoxystearic acid. It is presumablyobtainable from the reaction of peracetic acid with the glyceryltri-ricinoleate of castor oil. The crude thick brown oil obtained afterthe reaction was water insoluble, but completely soluble in chloroform.After being washed well with water and vacuum dried, it was found byanalysis to contain 0.3% oxirane (equivalent to approximately 90%reaction) and a chloride equivalent weight of 479. The calculated valuefor the equivalent weight of a trishydrazinium chloride was 403.8. Onthis basis, the product appears to be an unresolvable mixture of bis andtrishydrazinium chlorides, one of which has the probable structure:

16 ylaminobenzaldehyde test. The structure of the new product is shownbelow:

H NHCQHE Example XXI A 0.05 mole quantity of acetone azine and a 0.1mole quantity of propylene oxide were dissolved in benzene andcautiously treated dropwise with 10 ml. of an anhydrous dioxane solutioncontaining 0.05 mole of dry HBr. The reaction mixture was refluxed for30 minutes, cooled and filtered to give a poor yield of1,2-bis-(isopropylidenel-fl-hydroxypropyl)azinium bromide whichdecomposed at about 211 C. The new product was readily hydrolyzed bywater to acetone and (Z-hydroxypropyl)hydrazine hydrobromide. Itsstructural formula is shown hereunder:

My new reaction afiords a quicker, more convenient method of makinghydroxyalkyl hydrazinium salts than the standard alkylation techniqueknown to. the prior art. I have already indicated that the variety ofalkylating agents available for use in the prior art process is somewhatlimited. Moreover, by that process there are numerous possibilities ofcompeting side reactions which preclude obtaining high yields of thedesired product. Because of such side reactions, more complex work-upand purification procedures are required. My new reaction is relativelyclean; viz: there is little danger of undesirable side reactions.Furthermore, it is more adaptable to producing compounds of highmolecular weight and compounds containing negatively substituted alkylgroups, e.g. cyano, carbonyl, carboxy, nitro, sulfonyl, andphosphonyl-containing alkyl groups.

The use of oxiranes as a reactant makes available a greater variety ofultimate products. For example, there are no other alkylating agentscorresponding to the anhydro sugars or cyclohexylspiro'oxira-ne.

This application is a continuation in part of my c0- pending applicationS.N. 640,584 filed February 18, 1957, now US. Patent No. 2,899,424. Inthat application I described certain novel compounds useful asintermediates for making pharmacologically active hydrozinium salts.These intermediates are easily made by the process of the presentinvention. The pharmaceuticals derived from them are frequently used inpharmacological work [oHawmnoHoHro tz-(oHmooaomhono-ii-(oumoH-OH-OErCH-(GHMOH,

l OCGH: o H 0 30m 201- O III-(CB5): O

Example XX 0 as acid solutions of their hydrochloric acid salts. Since-A 0.05 mole portion of acetaldehyde phenylhydrazone and an equimolarquantity of benzyloxirane were refluxed in 40 ml. dioxane. The mixturewas saturated with dry HCl for 15 minutes and then refluxed for anadditional 30 minutes. It was cooled to l5-20 C. and allowed to standover night. Filtration gave crude yellowish brown2-phenyl-l-acetylidene-l-(2-hydroxy 3 phenylpropyl) hydrazoniumchloride. This new product melted at about 206 C. with decomposition. Itwas soluble in chloroform, but poorly soluble in water. Suspension inwater engendered a small amount of CH CHO and a change in form of solidto a rapidly air-oxidizable substance. Boiling with strong HCl gave nophenylhydrazine hydrochloride as shown by the failure of the sensitivedimethsired activity because of alkaline hydrolysis. Generallyspeaking,the salts made by the process of the present invention and thepharmaceutical derivatives made from these salts have marked stabilityto alkali and alkaline media. For example, the hydrazinium chloridesmade by the present process can be recovered unchanged from media ofcaustic soda alkalinity. This single major advantage is actually twofold, since (1) it means that the pharmaceutical salts can be used assuch in alkaline physiological fluids without precipitation and (2)these salts can be compounded into pharmaceuticalformulations which arealkaline in nature without fear of precipitation caused byincompatibility. i

The quarternizecl hydrazine derivatives have an addi-' tional desirablepharmacological property, cholinergic or anticholinergic effects on thenervous system, according to the nature of the substituents.Pharmaceutical utility does not imply complete equivalence betweensubstituent groups. Even when the same psychological efifect is producedby structurally difierent hydrazinium compounds, they are not usuallyequivalent because of marked differences in therapeutic dose range,tolerability range and extent of concomitant eifects and ease ofcompounding and availability; to mention a few of the variable factors.For example, aralkyl esters of will show greater anti-spasmodic actionin general than straight aryl or alkyl esters.

Compounds prepared by the method of the present invention are alsouseful as novel detergents, e.g.

hacteriocides, softeners, antistatic agents, emulsifiers and polymeringredients. termediates for the preparation of novel polymers. Thus Ihave discovered that acylation of dialcohols prepared by my reactionwith dibasic acids or their equally func- Certain others make excellentin- 18 wherein R R R and R are independently selected from the groupconsisting of hydrogen and alkyl, hydroxyalkyl, cycloalkyl aryl andaralkyl radicals; R and R taken together, to form a carbocyclic ringstructure; R and R taken separately, are members of the group consistingof lower alkyl, phenyl lower .alkyl and hydroxy lower alkyl radicals; Rand R taken together with the nitrogen on which they are bothsubstituents,

form a heterocyclic ring structure selected from the group consisting ofmorpholine, piperidine, piperazine and pyrrolidine; and X is an anionselected from the group consisting of chloride, bromide, iodide,sulfate, phosphate, nitrate, benzenesulfonate, monomethyl sulfate andmonphenyl phosphate; said process comprises subjecting a hydrazine saltof the general formula R R NNH -HX to the action of an oxirane of thegeneral formula and separating the said 1,1,1-tn'substituted hydraziniumsalt thus formed iirom the reaction mixture.

8. A process according to claim 7 wherein R R R and R are hydrogen, Rand R are lower alkyl and X is chloride.

9. A process according to claim 7 wherein R is aryl, R R and R arehydrogen, R is phenyl lower alkyl, R;

tioning derivatives (acid chlorides, anhydrides, etc.) yield is loweralkyl and X is chloride.

new types of polyelectrolytes:

10. A process according to claim 7 wherein R R Such products show markedpromise as anti-oxidants, fiocculants, anti-static agents, and textileanimalizers.

I claim:

1. A process according to claim 7 wherein the oxirane is introduced intothe reaction mixture in the vapor phase.

2. A process according to claim 1 wherein the molar ratio of oxirane tohydrazine is less than 1.

3. A process according to claim 2 wherein the reaction temperature ismaintained between 10 and 80 C.

4. A process according to claim 7 wherein the reaction is conductedunder substantially anhydrous conditions.

5. A process according to claim 4 wherein the reaction temperature ismaintained between 200 C.

6. A process according to claim 7 wherein the reaction is conducted inthe medium of an alcoholic solvent.

7. A process for preparing 1,1,1-trisubstituted hydrazinium salts of thegeneral formula:

5 R and R are hydrogen, R is hydroxy lower alkyl, R,

is lower alkyl and X is sulfate.

11. A process according to claim 7 wherein R is hydroxyalkyl, R R and Rare hydrogen, R and R together with the nitrogen on which they are bothsub- 55 stituents form a piperidine ring and X is chloride.

12. A process according to claim 7 wherein R and R are hydrogen, R and Rare alkyl, R and R are lower alkyl and X is chloride.

References Cited in the file of this patent UNITED STATES PATENTS GeverNov. 24, 1953 UNITED STATES PATENT OFFICE Certificate of CorrectionPatent No. 2,953,570 September 20, 1960 Bernard Rudner It is herebycertified that error appears in the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 3, lines 23 to 26, the formula should appear as shown belowinstead of as in the patent:

on, on,

oH, -o ooH, \O/

column 14, lines 33 to 38, the cation should be shown with a doublepositive charge and the anion should be shown as 2C1; same column 14,lines 45 to 51, the cation should be shown with a double positive chargeand the anion should be shown as 2nGl; column 15, lines 25 to 29, thecation should be shown with a double positive charge and the anionshould be shown as 201-; columns 15 and 16, lines 51 to 59, thestructural formula should appear as shown below instead of as in thepatent:

Signed and sealed this 8th day of May 1962.

[SEAL] Attest: v ERNEST W. SWIDER, DAVID L. LADD, Attesting Oficer.Commissionew of Patents.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No.2,953,570 September 20, 1960 Bernard Rudner It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 3, lines 23 to 26, the formula shouldappear as shown belowinstead of as in the patent:

column 14, lines 33 to 38, the cation should be shown with a doublepositive charge and the anion should be shown as 2C1; same column 14,lines 45 to 51, the cation should be shown with a double positive chargeand the anion should be shown as 2nCl; column 15, lines 25 to 29, thecation should be shown with a double positive charge and the anionshould be shown as 201-; columns 15 and 16, lines 51 to 59, thestructural formula should appear as shown below instead of as in thepatent:

H H 0 [CH3(CH2)|CHCHl- -(CH2)7COlOHilflCHIF-h-(CHI)1Cg-OH-CH2CH(CH7)ICH:201- o H N- om 0 000B. 0=C|3 IIIHI i H, V Signed and sealed this 8th dayof May 1962.

[SEAL] Attest: v ERNEST W. SWIDER, DAVID L. LADD,

Attesting Ofioer. Gammissz'oner of Patents.

7. A PROCESS FOR PREPARING 1,1,1-TRISUBSTITUTED HYDRAZINIUM SALTS OF THEGENERAL FORMULA:
 11. A PROCESS ACCORDING TO CLAIM 7 WHEREIN R1 ISHYDROXYLALKYL, R2, R3, AND R4 ARE HYDROGEN, R5 AND R6 TOGETHER WITH THENITROGEN ON WHICH THEY ARE BOTH SUBSTITUENTS FORM A PIPERIDINE RING ANDX IS CHLORIDE.